PURPOSE: To assess the safety and feasibility of direct vitrectomy-sparing subretinal injection for gene delivery in a large animal model. METHODS: The experimental Liběchov minipigs were used for subretinal delivery of a plasmid DNA vector (pS/MAR-CMV-copGFP) with cytomegalovirus (CMV) promoter, green fluorescent protein (GFP) reporter (copGFP) and a scaffold/matrix attachment region (S/MAR) sequence. The eyes were randomized to subretinal injection of the vector following pars plana vitrectomy (control group) or a direct injection without prior vitrectomy surgery (experimental group). Intra- and post-operative observations up to 30 days after surgery were compared. RESULTS: Six eyes of three mini-pigs underwent surgery for delivery into the subretinal space. Two eyes in the control group were operated with a classical approach (lens-sparing vitrectomy and posterior hyaloid detachment). The other four eyes in the experimental group were injected directly with a subretinal cannula without vitrectomy surgery. No adverse events, such as endophthalmitis, retinal detachment and intraocular pressure elevation were observed post-operatively. The eyes in the experimental group had both shorter surgical time and recovery while achieving the same surgical goal. CONCLUSIONS: This pilot study demonstrates that successful subretinal delivery of gene therapy vectors is achievable using a direct injection without prior vitrectomy surgery.

Center for Eye Research and Innovative Diagnostics Department of Ophthalmology Oslo University Hospital and Institute for Clinical Medicine University of Oslo Oslo Norway

Department of Ophthalmology Charles University Prague and the Kralovske Vinohrady University Hospital Prague Czech Republic

Department of Ophthalmology Justus Liebig University Giessen Eye Clinic University Hospital Giessen and Marburg GmbH Giessen Germany

Department of Ophthalmology Oslo University Hospital Kirkeveien 166 Oslo Norway

Department of Ophthalmology University of Split School of Medicine and University Hospital Centre Split Croatia

Department of Vitreoretinal Surgery and Research and Innovation Moorfields Eye Hospitals UAE Abu Dhabi

German Cancer Research Center Heidelberg Germany

Karl Landsteiner Institute for Retinal Research and Imaging Vienna Austria

Libechov Institute of Animal Physiology and Genetics Czech Academy of Sciences Libechov Czech Republic

Moorfields Eye Hospital NHS Foundation Trust London United Kingdom

The Francis Crick Institute London United Kingdom

UCL Institute of Ophthalmology London United Kingdom

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